CD122 is a 525 amino acid-long type I membrane protein that is expressed on T cells, NK cells, monocytes and a subset of B cells (Zamai, et al, J. Biol. Regul. Homeost. Agents 15:95-97 (2001)). The CD122 molecule is an integral part of the receptor for interleukin 2 (IL-2) and interleukin 15 (IL-15), two type I cytokines. CD122, also referred to as the β chain of the IL-2 and IL-15 receptors, combines with other receptor subcomponents to generate receptors that exhibit precise cytokine specificity and affinity. Molecules that functionally associate with CD122 on the cell surface include CD25 (also known as the IL-2 receptor α chain or IL-2Rα), CD132 (also referred to as the common γ or γc chain), and IL-15 receptor α chain (also referred to as IL-15Rα; not yet assigned a CD designation) (Waldmann, Nat. Rev. Immunol. 6:595-601 (2006)). CD122 in combination with CD132 forms a receptor that exhibits an intermediate level of affinity (intermediate affinity receptor) for both IL-2 (KD=˜1 nM) and IL-15 (KD=˜10 nM). CD122 associated with both CD25 and CD132 results in a receptor with high affinity (KD=˜10 pM) specific for IL-2, while CD122 in combination with IL-15Rα and CD132 generates a high affinity receptor (KD=˜10 pM) for IL-15 (Ma, A., et al., Annu. Rev. Immunol. 24: 657-679 (2006)).
IL-2 and IL-15 share the capacity to stimulate the proliferation of T lymphocytes, but each possesses unique activities in the maintenance of the immune system. IL-2 plays a role limiting T cell reactivity by priming activated T cells for apoptosis, whereas IL-15 is required for the development of NK cells and the development and maintenance of CD8+ memory T cells (Waldmann, Nat. Rev. Immunol. 6:595-601 (2006)). These two cytokines also exhibit a fundamental difference in the means by which they interact with their respective receptor components. IL-2 signaling occurs when the soluble cytokine interacts with either the intermediate or high affinity IL-2 receptor on the surface of a cell. This soluble cytokine delivery, in which a cytokine secreted by either the same or a distinct cell interacts with all receptor subcomponents on a single cell's surface, is the mechanism by which all type I cytokines, except IL-15, transmit their signals. In contrast, IL-15 signaling is carried out via presentation of IL-15 bound to IL-15Rα on the surface of one cell to another cell expressing the CD122 and CD132 molecules. This is referred to as trans-presentation. Trans-presentation is the mechanism by which IL-15 bound to the IL-15Rα receptor sub-component, or a fragment thereof, either soluble or bound to one cell, can be presented to a distinct cell expressing the remaining receptor subcomponents (CD122 and CD132) and resulting in IL-15 signaling. The affinity of isolated IL-15Rα, or fragments thereof, for IL-15 is high (KD=˜10 pM) and it is believed that IL-15 and IL-15Rα associate in the endoplasmic reticulum and are transported to the cell surface as a complex for trans-presentation to other cells expressing CD122 and CD132 on the surface. Cis-presentation occurs when IL-15 interacts with CD122, CD132 and IL-15Rα that are expressed on the same cell. The vast majority of IL-15 signaling is mediated via trans-presentation, while cis-presentation plays a minor role, and little or no signaling occurs by the delivery of soluble IL-15 (Stonier and Schluns, Immunol. Lett. 127:85-92 (2010); Ma et al., Annu. Rev. Immunol. 24: 657-679 (2006); Dubois et al., Immunity 17:537-547 (2002)).
As well as sharing the basic structural similarities of the type I cytokines, some functional activities, and certain receptor subcomponents, IL-2 and IL-15 has each been associated with a variety of immune-mediated diseases. For instance, inhibition of IL-2 activity by targeting the α chain of the IL-2 receptor (CD25) with a monoclonal antibody is an effective immunomodulatory strategy that is currently approved for acute kidney transplant rejection (Vincenti et al., New Engl. J. Med. 338:161-5 (1998)). Additionally, therapeutic benefits of anti-CD25 approaches have also been reported in clinical trials that target asthma (Busse et al., Am. J. Respir. Crit. Care Med. 178:1002-1008 (2008)), uveitis (Yeh et al., J. Autoimmun. 31:91-97 (2008)) and multiple sclerosis (Rose et al., Neurology, 69:785-789 (2007)), implicating IL-2 involvement in these conditions. An IL-15-specific monoclonal antibody has been reported to have positive therapeutic effect in a clinical trial for rheumatoid arthritis (Baslund et al., Arthritis Rheum. 52:2686-2692 (2005)), and reported to have efficacy in animal models of psoriasis (Villadsen et al., J. Clin. Invest. 112:1571-1580 (2003)), celiac disease (Maiuri et al., Gastroenterology 119:996-1066 (2000)), and systemic lupus erythematosus (Bo et al., Scand. J. Immunol. 69:119-129 (2009)). Mouse monoclonal antibodies against human CD122 have been generated from mice immunized with human T cell lines and subsequently identified as being specific for the β chain of the IL-2 receptor by a variety of techniques (Tsudo et al., Proc. Natl. Acad. Sci. USA 86:1982-1986 (1989); Takeshita et al., J. Exp. Med. 169:1323-1332 (1989); Fung et al., J. Immunol. 147:1253-1260 (1991)). These anti-CD122 monoclonal antibodies inhibited IL-2-dependent proliferation on cells bearing the intermediate affinity IL-2 receptor, but they were not able to effectively inhibit IL-2-dependent proliferation on cells bearing the high affinity IL-2 receptor. Furthermore, no anti-CD122 monoclonal antibodies have been reported that effectively inhibit trans-presentation of IL-15.
One anti-CD122 antibody, Mik-β1 (Tsudo et al., Proc. Natl. Acad. Sci. USA 86:1982-1986 (1989)), has been tested as a therapy for T cell large granular lymphocyte leukemia (Morris et al., Proc. Nat. Acad. Sci. USA 103:401-406 (2006)). Mik-β1 has also been humanized, and this version, HuMik-β1 (Hakimi et al., J. Immunol. 151:1075-1085 (1993)) has been reported to prolong cardiac allografts in non-human primates (Tinubu et al., J. Immunol. 153: 4330-4338 (1994)).